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Hellinger R, Thell K, Vasileva M, et al. Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins. Front Chem. 2017;5:73doi: 10.3389/fchem.2017.00073.
Hellinger, R., Thell, K., Vasileva, M., Muhammad, T., Gunasekera, S., Kümmel, D., Göransson, U., Becker, C. W., & Gruber, C. W. (2017). Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins. Frontiers in chemistry, 573. https://doi.org/10.3389/fchem.2017.00073
Hellinger, Roland, et al. "Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins." Frontiers in chemistry vol. 5 (2017): 73. doi: https://doi.org/10.3389/fchem.2017.00073
Hellinger R, Thell K, Vasileva M, Muhammad T, Gunasekera S, Kümmel D, Göransson U, Becker CW, Gruber CW. Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins. Front Chem. 2017 Oct 11;5:73. doi: 10.3389/fchem.2017.00073. eCollection 2017. PMID: 29075625; PMCID: PMC5641551.
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Front Chem. 2017 Oct 11;5:73. doi: 10.3389/fchem.2017.00073. eCollection 2017.

Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins.

Frontiers in chemistry

Roland Hellinger, Kathrin Thell, Mina Vasileva, Taj Muhammad, Sunithi Gunasekera, Daniel Kümmel, Ulf Göransson, Christian W Becker, Christian W Gruber

Affiliations

  1. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  2. Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
  3. School of Biology/Chemistry, University of Osnabrück, Osnabrück, Germany.
  4. Department of Chemistry, Institute of Biological Chemistry, University of Vienna, Vienna, Austria.
  5. School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St. Lucia, QLD, Australia.

PMID: 29075625 PMCID: PMC5641551 DOI: 10.3389/fchem.2017.00073

Abstract

Target deconvolution is one of the most challenging tasks in drug discovery, but a key step in drug development. In contrast to small molecules, there is a lack of validated and robust methodologies for target elucidation of peptides. In particular, it is difficult to apply these methods to cyclic and cysteine-stabilized peptides since they exhibit reduced amenability to chemical modification and affinity capture; however, such ribosomally synthesized and post-translationally modified peptide natural products are rich sources of promising drug candidates. For example, plant-derived circular peptides called cyclotides have recently attracted much attention due to their immunosuppressive effects and oral activity in the treatment of multiple sclerosis in mice, but their molecular target has hitherto not been reported. In this study, a chemical proteomics approach using photo-affinity crosslinking was developed to determine a target for the circular peptide [T20K]kalata B1. Using this prototypic nature-derived peptide enabled the identification of a possible functional modulation of 14-3-3 proteins. This biochemical interaction was validated via competition pull down assays as well as a cellular reporter assay indicating an effect on 14-3-3-dependent transcriptional activity. As proof of concept, the presented approach may be applicable for target elucidation of various cyclic peptides and mini-proteins, in particular cyclotides, which represent a promising class of molecules in drug discovery and development.

Keywords: chemical proteomics; cyclic protein; cyclotides; peptide-protein interaction; photo-affinity labeling

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